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An Update on Pharmaceutical Strategies for Oral Delivery of Therapeutic Peptides and Proteins

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An Update on Pharmaceutical Strategies for Oral Delivery of Therapeutic Peptides and Proteins University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 11-2019 An Update on Pharmaceutical Strategies for Oral Delivery of Therapeutic Peptides and Proteins Nirnoy Dan University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Dan, Nirnoy (https://orcid.org/0000-0003-3335-9792), "An Update on Pharmaceutical Strategies for Oral Delivery of Therapeutic Peptides and Proteins" (2019). Theses and Dissertations (ETD). Paper 506. http://dx.doi.org/10.21007/etd.cghs.2019.0491. This Thesis is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. An Update on Pharmaceutical Strategies for Oral Delivery of Therapeutic Peptides and Proteins Abstract Peptides and proteins are imperative for the human body and play crucial roles in governing various bio- chemical processes. Recent advances in molecular biology and biochemistry helped in understanding the role of these endogenous macromolecules in different pathological and disease conditions. Currently, small molecule drugs (< 900dalton) in comparison to the therapeutic peptides and proteins-based drugs (TPP) dominate pharmaceutical market. However, the game is changing with the recent advances of biotechnological tools like recombinant DNA technology, solid phase protein synthesis etc., which enabled large-scale production of therapeutic peptides and proteins. The Success of Human Insulin, the first FDA approved commercial recombinant protein based therapeutic in 1982, revolutionized the field of TPPs. The number of FDA approved TPPs reached about to ~239 in 2017 compared to where it was only ~130 in 2008. Rapid progress in this sector can be attributed to several advantages of proteins and peptides over small molecule drugs both financially and clinically. From a clinical perspective, proteins and peptides are inherently more specific ot the target site than the small molecules drugs, which lead to less interferences with normal biological system of the patient and caused minimal off-target side effects. A handful of proteins which are used for different clinical complications are less immunogenic because they are produced in the body naturally. Furthermore, proteins and peptides also take part in several complex and complicated biological processes, which is difficulto t be to be mimicked by the small molecule drugs. From a financial standpoint, median otalt pre-market development times were shorter for biologics (10.6 years) than the small molecules drugs (12.6 years) estimated using Merck Index. In 2009, US Congress passed the Biologics Price Competition and Innovation Act (BPCIA) which gave new biologics 12 years of guaranteed exclusivity. The most commonly utilized routes for administering TPPs are I.V, I.P or I.M injections, which largely suffer from patient compliances. There are ~350 TPPs under clinical development and among them only 2 are given orally which is Interferon-α and Human growth hormone. Currently, most efforts in both industry and academia are centered around enhancing bioavailability of orally administered TPPs which typically are less than 1%. Oral administration is the non-invasive, most preferred route of drug administration for the patients. Furthermore, oral dosage forms are cheaper to manufacture as well as to administer, because they do not need to be produced under sterile conditions or administered in clinics. However, unfavorable physicochemical characteristics of TPPs like high molecular weight, hydrophilicity, poor stability in the physiological conditions, short biological half-life, low permeability through the epithelial barrier in the small intestine put up a massive barrier in the development of orally available dosage forms of TPPs. In this review, we will discuss the challenges associated with oral delivery of TPPs and the ongoing efforts to solve them. Document Type Thesis Degree Name Master of Science (MS) Program Pharmaceutical Sciences Research Advisor Hassan Almoazen, Ph.D. Keywords Biologics Delivery, Formulation, Oral Delivery, Proteins and Peptides Subject Categories Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences This thesis is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/506 UNIVERSITY OF TENNESSEE HEALTH SCIENCE CENTER MASTER OF SCIENCE THESIS An Update on Pharmaceutical Strategies for Oral Delivery of Therapeutic Peptides and Proteins Author: Advisor: Nirnoy Dan Hassan Almoazen, Ph.D. A Thesis Presented for The Graduate Studies Council of The University of Tennessee Health Science Center in Partial Fulfillment of the Requirements for the Master of Science degree from The University of Tennessee in Biomedical Sciences: Molecular and Systems Pharmacology College of Graduate Health Sciences December 2019 Copyright © 2019 by Nirnoy Dan. All rights reserved. ii DEDICATION To my respected parents, Mrs. Swapna Dan and Mr. Nilachal Dan, and my grandparents Mrs. Madhuri Dikpati and Mr. Laxmi Narayan Dikpati for their unconditional love, inspiration and constant encouragement. iii ACKNOWLEDGEMENTS I would first like to thank my advisor Dr. Hassan Almoazen. The door to Prof. Almoazen’s office was always open whenever I had a question about my research or writing. He consistently allowed this paper to be my own work and steered me in the right the direction whenever he thought I needed it. I am truly thankful to him for the opportunities, motivation, guidance and support he gave to me throughout the research period. I would also like to thank my committee members Drs. Duane D. Miller and Isaac O. Donkor. Without their passionate participation and input, the validation survey could not have been successfully conducted. Finally, I must express my very profound gratitude Department of Pharmaceutical Sciences and College of Graduate health Sciences, UTHSC for their administrative and financial support. iv ABSTRACT Peptides and proteins are imperative for the human body and play crucial roles in governing various bio-chemical processes. Recent advances in molecular biology and biochemistry helped in understanding the role of these endogenous macromolecules in different pathological and disease conditions. Currently, small molecule drugs (<900dalton) in comparison to the therapeutic peptides and proteins-based drugs (TPP) dominate pharmaceutical market. However, the game is changing with the recent advances of biotechnological tools like recombinant DNA technology, solid phase protein synthesis etc., which enabled large-scale production of therapeutic peptides and proteins. The Success of Human Insulin, the first FDA approved commercial recombinant protein based therapeutic in 1982, revolutionized the field of TPPs. The number of FDA approved TPPs reached about to ~239 in 2017 compared to where it was only ~130 in 2008. Rapid progress in this sector can be attributed to several advantages of proteins and peptides over small molecule drugs both financially and clinically. From a clinical perspective, proteins and peptides are inherently more specific to the target site than the small molecules drugs, which lead to less interferences with normal biological system of the patient and caused minimal off-target side effects. A handful of proteins which are used for different clinical complications are less immunogenic because they are produced in the body naturally. Furthermore, proteins and peptides also take part in several complex and complicated biological processes, which is difficult to be to be mimicked by the small molecule drugs. From a financial standpoint, median total pre-market development times were shorter for biologics (10.6 years) than the small molecules drugs (12.6 years) estimated using Merck Index. In 2009, US Congress passed the Biologics Price Competition and Innovation Act (BPCIA) which gave new biologics 12 years of guaranteed exclusivity. The most commonly utilized routes for administering TPPs are I.V, I.P or I.M injections, which largely suffer from patient compliances. There are ~350 TPPs under clinical development and among them only 2 are given orally which is Interferon-α and Human growth hormone. Currently, most efforts in both industry and academia are centered around enhancing bioavailability of orally administered TPPs which typically are less than 1%. Oral administration is the non-invasive, most preferred route of drug administration for the patients. Furthermore, oral dosage forms are cheaper to manufacture as well as to administer, because they do not need to be produced under sterile conditions or administered in clinics. However, unfavorable physicochemical characteristics of TPPs like high molecular weight, hydrophilicity, poor stability in the physiological conditions, short biological half-life, low permeability through the epithelial barrier in the small intestine put up a massive barrier in the development of orally available dosage forms of TPPs. In this review, we will discuss the challenges associated with oral delivery of TPPs and the ongoing efforts to solve them. v TABLE OF CONTENTS CHAPTER 1. INTRODUCTION .....................................................................................1 CHAPTER 2. CHALLENGES
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